title: Tumor necrosis factor-α inhibits angiotensin II receptor type 1 expression in dorsal root ganglion neurons via β-catenin signaling.
abstract: Both tumor necrosis factor (TNF)-α and the angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) axis play important roles in neuropathic pain and nociception. In the present study, we explored the interaction between the two systems by examining the mutual effects between TNF-α and the Ang II/AT1 receptor axis in dorsal root ganglion (DRG) neurons. Rat DRG neurons were treated with TNF-α in different concentrations for different lengths of time in the presence or absence of transcription inhibitor actinomycin D, TNF receptor 1 (TNFR1) inhibitor SPD304, β-catenin signaling inhibitor CCT031374, or different kinase inhibitors. TNF-α decreased the AT1 receptor mRNA level as well as the AT1a receptor promoter activity in a dose-dependent manner within 30 h, which led to dose-dependent inhibition of Ang II-binding AT1 receptor level on the cell membrane. Actinomycin D (1 mg/ml), SPD304 (50 μM), p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 (25 μM), and CCT031374 (50 μM) completely abolished the inhibitory effect of TNF-α on AT1 receptor expression. TNF-α dose-dependently increased soluble β-catenin and phosphorylated GSK-3β levels, which was blocked by SPD304 and PD169316. In DRG neurons treated with AT2 receptor agonist CGP421140, or Ang II with or without AT1 receptor antagonist losartan or AT2 receptor antagonist PD123319 for 30 h, we found that Ang II and Ang II+PD123319 significantly decreased TNF-α expression, whereas CPG421140 and Ang II+losartan increased TNF-α expression. In conclusion, we demonstrate that TNF-α inhibits AT1 receptor expression at the transcription level via TNFR1 in rat DRG neurons by increasing the soluble β-catenin level through the p38 MAPK/GSK-3β pathway. In addition, Ang II appears to inhibit and induce TNF-α expression via the AT1 receptor and the AT2 receptor in DRG neurons, respectively. This is the first evidence of crosstalk between TNF-α and the Ang II/AT receptor axis in DRG neurons.
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Hunan Provincial Tumor Hospital, Affiliated Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: J-Q
authors.initials: JQ
authors.lastname: Yan
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Z-B
authors.initials: ZB
authors.lastname: Song
authors.affiliation: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China. Electronic address: qulianguo@hotmail.com.
authors.forename: Q-L
authors.initials: QL
authors.lastname: Guo
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002839:Chromans; D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D011799:Quinazolines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; C527814:SPD-304; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D000804:Angiotensin II; C073402:PD 123319; D003609:Dactinomycin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole
keywords: angiotensin II receptor type 1; dorsal root ganglion neuron; glycogen synthase kinase-3β; p38 mitogen-activated protein kinase; tumor necrosis factor-α; β-catenin